The invention relates to novel mixed inhibitors of neprilysine and aminopeptidase N with prolonged action.
It is known that enkephalins -Tyr-Gly-Gly-Phe-Met and Tyr-Gly-Gly-Phe-Leu- are endogenous ligands of the μ and δ opoid receptors, the localizations of which (Waksman et al. (1985) Proc. Natl. Acad. Sci. USA, 83, 1523-1527) and the functions of which are different: the μ receptors are essentially involved in the transmission of nociceptive impulses and the δ receptors in the regulation of mood and adaptation behaviors, in particular to stress (as reviewed in Noble et Roques, 2007, Expert Opin. Ther. Targets, 11, 145-159), (Jutkiewicz et al., 2006, Eur. J. Pharmacol., 531, 151-159). Intracerebroventricular administration of exogenous enkephalins induces a transient analgesic response because of the very rapid catabolism of these peptides by two enzymes, neprilysine (NEP, E.C. 3.4.24.11) which cleaves the Gly3-Phe4 bond of enkephalins and aminopeptase N (APN, E.C. 3.4.11.2) which releases N-terminal tyrosine (as reviewed in Roques et al., 1993, Pharmacol. Rev. 45, 88-146).
Mixed inhibitors of these two enzymes are known which, by completely protecting the endogenous enkephalins from their enzymatic degradation, reveal the pharmacological, in particular analgesic and antidepressive activities of enkephalins. The mixed inhibitors of both of these enzymatic activities, as described in the prior art, are compounds with a hydroxamate function (FR 2 518 088 and FR 2 605 004), aminophosphine compounds (FR 2 755 135 and FR 2 777 780) and aminoacid derivatives (FR 2 651 229 and WO2007/048787). In the case of compounds with a hydroxamate function, good activity in vitro and in vivo after administration via an intracerebroventricular route was observed (Eur. J. Pharmacol. 102, (1984), 525-528; Eur. J. Pharmacol., 165, (1989), 199-207; Eur. J. Pharmacol., 192, (1991), 253-262); significant activity was also able to be demonstrated after intravenous administration (iv) in an arthritic rat model (Brain Research, 497, (1989), 94-101). In the case of phosphine derivatives and aminoacid derivatives described in the application FR 2 651 229, good activity in vivo was demonstrated after administration via an iv route, when the investigated molecules were solubilized in a mixture of oil, ethanol and water (J. Med. Chem., 43, (2000), 1398-1408; J. Med. Chem., 44, (2001), 3523-3530; J. Pharm. Exp. Ther., 261, (1992), 181-190). The aminoacid derivatives described in the application WO2007/048787 are mixed inhibitors soluble in an aqueous medium, which have analgesic properties after administration via an iv route and via an oral route into laboratory animals, at doses compatible with administration into humans. Unfortunately, these molecules in animal pain models have a short action period (about 40 min) with a maximum around 10 min. and return to normal conditions after 15-30 min, which may represent a significant handicap for therapeutic uses, if the action period was of the same order in humans.
It will be recalled that the action period is the time during which, at its action site, the active ingredient contained in the drug produces its therapeutic or preventive effect. It is then eliminated by the organism. With the purpose of improving the action period of these molecules, modifications in their structures were made.
One of the objects of the invention is to provide novel water-soluble compounds capable of inhibiting together both enzymatic activities responsible for the degradation of enkephalins and of expressing their pharmacological properties on central and peripheral tests after administration, notably via an iv route or via an oral route, and for which the action period on the laboratory animal is equal to or longer than 120 min. Consequently, the novel compounds have properties of morphine substances, in particular analgesia, beneficial effects on behavior (decrease in the emotional component of pain and in antidepressive responses) and peripheral (antidiarrheic, antitussive, anti-inflammatory) effects without having the major drawbacks thereof (tolerance, physical and psychic addictions, respiratory depression, constipation, nausea, etc. . . . ).
Further, inflammatory, neurogenic and neuropathic pains, for which the peripheral component is significant, and nociceptive pains are reduced or even eliminated by the compounds of the invention notably administered via an oral route, and this without the latter being forced to attain the central nervous system. This very interesting but unexpected result was formerly demonstrated by the use of an antagonist—methylaloxonium—incapable of entering the brain (Milne R. J. et al. (1990) Neuroscience Lett. 114, 259-264). This totally reduces all the effects due to the stimulation of cerebral opioid receptors by the compounds of the invention, without altering the analgesic effects of the compounds on these pains, in particular on neurogenic, neuropathic, neuroinflammatory and nociceptive pains.
Another object of the invention is to propose combinations between known compounds for their antinociceptive properties but having harmful secondary effects at strong doses, and the compounds claimed in the present invention. These combinations more particularly relate to morphine and its derivatives, Δ9-tetrahydrocannabinol (Δ9 THC) and its derivatives as well as derivatives of Gaba such as gabapentin or pregabalin. Indeed, strong potentialization of the antinociceptive responses obtained by combination of subactive doses of one of the compounds claimed in the present application and of one of the aforementioned analgesics (morphine, (Δ9 THC, gabapentin) was able to be ascertained.
The object of the invention is more particularly compounds having the following formula (I):R1NH—CH(R2)—CH2—S—S—CH2—C(R3)(R4)—CONH—C—(R5)(R6)—COOR7 
wherein:
R1 represents an (acyloxy)alkyl carbamate group—(CO)—O—C(R8)(R9)—OC(O)—R10, wherein                R8 and R9 independently of each other represent a hydrogen atom, an alkyl, aryl, arylakyl, cycloalkyl, cycloheteroalkyl, heteroalkyl, heteroaryl or heteroarylalkyl group; or        taken together, R8 and R9 may form a cycloalkyl with 5 or 6 members;        R10 represents an alkyl, aryl, arylalkyl, cycloalkyl, cycloheteroalkyl, heteroalkyl, heteroaryl or heteroarylalkyl group;R2 represents:        a linear or branched saturated hydrocarbon chain having 1 to 6 carbon atoms, optionally substituted with:        an OH, OR11, SH, SR11 or S(O)R11 radical, in each of these radicals, R11 represents a linear or branched hydrocarbon chain with 1 to 4 carbon atoms, a phenyl radical or a benzyl radical,        a phenyl or benzyl radical, optionally substituted with:                    1 to 5 halogen atoms, notably fluorine,            an OH, OR11, SH, SR11 or S(O)R11 radical, R11 having the same meaning as earlier,            a methylene radical substituted with a 5 or 6 members, aromatic or saturated, heterocycle, having as a heteroatom, a nitrogen or sulfur atom, optionally oxidized as an N-oxide or S-oxide,when R4 represents a hydrogen atom, R3 represents:                        a phenyl or benzyl radical optionally substituted with:        1 to 5 halogen atoms;        an SR11, S(O)R11 or OR11 radical, R11 having the same meaning as earlier;        an amino group optionally mono- or di-substituted with a cyclic or linear aliphatic group having 1 to 6 carbon atoms;        a heteroaryl with 5 or 6 members, the heteroatom being an oxygen, a sulfur or nitrogen atom;        a methylene group substituted with a 5 or 6 members, aromatic or saturated, heterocycle, the heteroatom being an oxygen, nitrogen or sulfur atom, the nitrogen and sulfur atoms may be oxidized as an N-oxide or S-oxide;when R4 is different from H, R3 and R4 taken together form a saturated cycle with 5 or 6 members;        
R5 and R6 independently of each other represent:                a hydrogen atom,        a linear or branched saturated hydrocarbon chain, having from 1 to 6 carbon atoms, optionally substituted with an OH, OR11, SH or SR11, COOH or COOR11 radical, in each of these radicals, R11 has the same meaning as earlier,        a phenyl or benzyl radical, optionally substituted with:        a linear or branched alkyl chain having 1 to 4 carbon atoms;        1 to 5 halogens, notably fluorine or bromine;        an OH, OR11, SH or SR11 radical, R11 having the definition as earlier;or taken together R5 and R6 from a saturated cycle with 5 or 6 members;        
R7 represents                a hydrogen atom;        a phenyl or benzyl radical optionally substituted with 1 to 5 halogens, notably fluorine;        a group of formula CR12(R13)C(O)OR14;        a group CR12(R13)OC(O)R14;        a group CR12(R13)OC(O)OR14;        
R12 and R13 independently of each other represent a hydrogen atom, an alkyl, aryl, arylalkyl, cycloalkyl, cycloheteroalkyl, heteroalkyl, heteroaryl or heteroarylalkyl group;
taken together R12 and R13 may form a cycloalkyl with 5 or 6 members.
R14 represents an alkyl, aryl, arylalkyl, cycloalkyl, cycloheteroalkyl, heteroalkyl, heteroaryl or heteroarylalkyl group;
as well as the addition salts of said compound (I) with pharmaceutically acceptable mineral or organic bases and each of its isomers, in particular its optical isomers (enantiomers and diastereoisomers).
For the “drug” portion of the molecule, i.e. the formula portion—NH—C*H(R2)—CH2—S—S—CH2—C*(R3)(R4)—CONH—C*(R5)(R6)—COO— the compounds according to the invention potentially have at most 3 asymmetric carbons, indicated by an asterisk, and which is reduced to a single centre of asymmetry when (R3)(R4) and (R5)(R6) form rings without any asymmetry. These centers are optically pure, with an absolute configuration like that of a natural aminoacid, i.e. an S configuration. The possible centers of asymmetry of the “prodrug” portions, i.e. for the substituents R1 and R7, are not resolved: these potential centers of symmetries may therefore be equally of R or S configuration.
The object of the invention is also addition salts of the compounds of formula (I), obtained with pharmacologically acceptable organic or mineral bases. In the present invention, “pharmaceutically acceptable” is meant to refer to what is useful in the preparation of a pharmaceutical composition, which is generally secure, non-toxic and neither biologically nor otherwise undesirable and which is acceptable for veterinary use as well as for human pharmaceutical use.
Further, “pharmaceutically acceptable salts” of a compound, are meant to refer to salts which have the desired pharmacological activity of the parent compound. Such salts comprise the salts formed when an acid proton present in the parent compound is either replaced with a metal ion, for example an alkaline metal ion, an earth alkaline metal ion; or coordinates with an organic or inorganic base. The acceptable organic bases comprise diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, and the like, or natural basic aminoacids (for example lysine, arginine, alanine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine) or non-natural basic aminoacids (such as pseudo-lysine). The acceptable inorganic bases in particular comprise aluminium hydroxide, calcium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and sodium hydroxide. Advantageously, the acid proton is displaced by a Na+ ion, notably by using sodium hydroxide.
Within the scope of the present invention, the expression “hydrocarbon chain” refers to linear or branched alkanes, alkenes, or alkynes. In particular, the expression “saturated hydrocarbon chain” refers to either linear or branched alkyl radicals including from 1 to 6 carbon atoms (C1-C6) or from 1 to 4 carbon atoms (C1-C4). As an example of alkyl radicals including 1 to 4 carbon atoms, mention may be made of methyl, ethyl, propyl, butyl, isopropyl, 1-methyl-ethyl, 1-methyl-propyl, 2-methyl-propyl radicals. As an example of alkyl radicals including from 1 to 6 carbon atoms, mention may further be made of pentyl, hexyl, 1-methyl-butyl, 1-methyl-pentyl, 2-methyl-butyl, 2-methyl-pentyl, 3-methyl-butyl, 3-methyl-pentyl, 4-methyl-pentyl or 1-ethyl-propyl, or 1-ethyl-butyl, 2-ethyl-butyl radicals.
The expression “unsaturated hydrocarbon chain” refers to linear or branched, alkenyl radicals (at least one double bond), for example vinyl, allyl radicals or the like, or alkenyl radicals (at least one triple bond) including from 2 to 6 carbon atoms, or from 2 to 4 carbon atoms. By the term “heteroalkyl”, is meant in the sense of the present invention, any hydrocarbon chain, as defined earlier, containing one or several heteroatoms, such as for example sulfur, nitrogen or oxygen atoms. By the term “cycloalkyl”, is meant in the sense of the present invention, any hydrocarbon ring, either saturated or not, but non-aromatic, with 3 to 7 members, in particular 5 or 6 members, such as cyclopentyl and cyclohexyl.
By the term “cycloheteroalkyl”, is meant in the sense of the present invention, any hydrocarbon ring, either saturated or not, but non-aromatic, with 5 to 7 members, containing one or more heteroatoms, such as for example sulfur, nitrogen or oxygen atoms. By the expression “aliphatic, cyclic or linear group”, is meant a “hydrocarbon chain” or a “cycloalkyl” as defined earlier. By the term “aryl”, is meant in the sense of the present invention, one or more aromatic rings having from 5 to 10 carbon atoms, which may be fused with each other. In particular, aryl groups may be monocyclic or bicyclic groups such as for example the phenyl or naphthyl group. Advantageously, the aryl group is a phenyl.
By the term “heteroaryl”, is meant in the sense of the present invention, any aromatic group comprising from 5 to 10 cyclic atoms, which are carbon atoms or one or more heteroatoms, such as for example sulfur, nitrogen or oxygen atoms. The heteroaryl according to the present invention may be formed by one or two fused rings. Examples of heteroaryl groups are quinolyl, isoquinolyl, imidazolyl, indolyl, pyridyl, triazinyl, thiazoyl, and thiophenyl groups.
The term “aralkyl” within the scope of the present invention, designates aryl radicals (as defined earlier) bound to alkyl radicals (as defined earlier) such as for example benzyl or phenethyl. The term “heteroaralkyl” within the scope of the present invention, refers to heteroaryl radicals (as defined earlier) bound to alkyl radicals (as defined earlier). By the term “heterocycle”, is meant a “cycloheteroalkyl” or a “heteroaryl” as defined earlier. As an example of aromatic or saturated heterocyclic rings with 5 or 6 atoms, having as a heteroatom a nitrogen or sulfur atom, mention may be made, but without any limitation, of the following radicals: thienyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, thiadiazolyl, the nitrogen and sulfur atoms being optionally oxidized as an N-oxide or S-oxide. As an example of aromatic or saturated heterocyclic rings with 5 or 6 atoms, having as a heteroatom an oxygen atoms, mention may be made, but without any limitation, of the following radicals: furyl, pyranyl, isoxazolyl, morpholinyl, furazanyl, oxazolyl, oxazolidinyl, oxazolinyl. The term “halogen” used here refers to a chlorine, bromine, iodine and fluorine atom.
The radical R1 advantageously represents an (acyloxy)alkyl carbamate group—(CO)—O—C(R8)(R9)—OC(O)—R10, wherein                R8 and R9 independently of each other represent a hydrogen atom or an alkyl group; and        R10 represents an alkyl group, in particular an isopropyl.        
The radical R2 advantageously represents an alkyl radical having from 1 to 4 carbon atoms, optionally substituted with an OR11, SR11 or S(O)R11 radical, in each of these radicals, R11 has the same meaning as earlier. R2 still more advantageously represents an alkyl radical having from 1 to 4 carbon atoms substituted with an SR11 or S(O)R11 radical R11 having the same meaning as earlier, in particular R11 represents a linear or branched saturated hydrocarbon chain with 1 to 4 carbon atoms and more advantageously a methyl group.
According to an advantageous alternative of the invention, the radical R4 represents a hydrogen atom. Within the scope of this alternative, the radical R3 advantageously represents:                a benzyl or phenyl radical,        a methylene radical substituted with an aromatic or saturated heterocycle with 5 or 6 atoms, having as a heteroatom a nitrogen or sulfur atom, optionally oxidized as an N-oxide or S-oxide.In particular the radical R4 represents a hydrogen atom and the radical R3 represents a benzyl radical or a methylene radical substituted with an aromatic or saturated heterocycle with 5 or 6 atoms, having as a heteroatom, a nitrogen or sulfur atom, optionally oxidized as an N-oxide or S-oxide, even more advantageously a benzyl radical.        
According to another advantageous alternative of the invention, the radicals R4 and R3 form together with the carbon which bears them a cycloalkyl with 5 or 6 members, in particular a cyclopentane or a cyclohexane. The radical R5 advantageously represents a hydrogen atom. The radical R6 advantageously represents a hydrogen atom or an alkyl radical having from 1 to 6 carbon atoms, even more advantageously 1 to 4 carbon atoms, optionally substituted with an OH, OR11, SH, or SR11, COOH or COOR11 radical, in each of these radicals, R11 has the same meaning as earlier. The radical R6 still more advantageously represents a hydrogen atom or an alkyl radical having from 1 to 6 carbon atoms, sill more advantageously 1 to 4 carbon atoms, substituted with an OH, SH, COOH or COOR11 radical, R11 having the same meaning as earlier.
The radical R7 advantageously represents:                a hydrogen atom;        a phenyl or benzyl radical;        an alkyl radical having from 1 to 4 carbon atoms;        a CR12(R13)O(CO)OR14 group, wherein R12, R13 and R14 have the same meaning as earlier, in particular R12 represents a hydrogen atom and R13 and R14 independently of each other represent a C1-C4 alkyl group optionally substituted with a methoxy group or a C5-C6 cycloalkyl group.In particular, the radical R7 represents a hydrogen atom or a benzyl radical.        
The invention in particular relates to the following compounds:    1-(1-{2-[(1-ethoxycarbonyloxy-ethoxy carbonylmethyl)-carbamoyl]-3-phenyl-propyldisulfanylmethyl}-3-methyl-sulfanyl-propylcarbamoyloxy)-ethyl isobutyric acid ester.    1-{1-[2-(benzyloxycarbonylmethyl-carbamoyl)-3-phenyl-propyl-disulfanylmethyl]-3-methylsulfanyl-propylcarbamoyloxy}-ethyl isobutyric acid ester.    1-{1-[2-(carboxymethyl-carbamoyl)-3-phenyl-propyldisulfanyl-methyl]-3-methylsulfanyl-propylcarbamoyloxy}-ethyl isobutyric acid ester.    1-(1-{2-[(1-ethoxycarbonyloxy-ethoxycarbonylmethyl)-carbamoyl]-3-phenyl-propyldisulfanylmethyl}-3-methane-sulfinyl-propylcarbamoloxy)-ethyl isobutyric acid ester.    1-{1-[2-benzyloxycarbonylmethyl-carbamoyl)-3-phenyl-propyl-disulfanylmethyl]-3-methanesulfinyl-propylcarbamoyloxy}-ethyl isobutyric acid ester.    1-{1-2[2-(carboxymethyl-carbamoyl)-3-phenyl-propyl-disulfanylmethyl]-3-methanesulfinyl-propylcarbamoyl-oxy}-ethyl isobutyric acid ester.    2-({1-[2-(1-isobutyryloxy-ethoxycarbonylamino)-4-methyl-sulfinyl-butyldisulfanylmethyl]-cyclopentanecarbonyl}-amino)-succinic acid.    2-({1-[2-(1-isobutyryloxy-ethoxycarbonylamino)-4-methyl-sulfanyl-butyldisulfanylmethyl]-cyclopentanecarbonyl}-amino)-succinic acid.    Benzyl 2-({1-[2-(1-isobutyryloxy-ethoxycarbonylamino)-4-methanesulfinyl-butyldisulfanylmethyl]-cyclopentanecarbonyl}-amino)-succinic acid ester    Benzyl 2-({1-[2-(1-isobutyryloxy-ethoxycarbonylamino)-4-methylsulfanyl-butyldisulfanylmethyl]-cyclopentanecarbonyl}-amino)-succinic acid.
According to an advantageous alternative of the invention, the following compounds are preferred:    1-{1-[2-(carboxymethyl-carbamoyl)-3-phenyl-propyldisulfanyl-methyl]-3-methylsulfanyl-propylcarbamoyloxy}-ethyl isobutyric acid ester.    1-{1-[2-benzyloxycarbonylmethyl-carbamoyl)-3-phenyl-propyl-disulfanylmethyl]-3-methanesulfinyl-propylcarbamoyloxy}-ethyl isobutyric acid ester.    1-{1-2[2-(carboxymethyl-carbamoyl)-3-phenyl-propyl-disulfanylmethyl]-3-methanesulfinyl-propylcarbamoyloxy}-ethyl isobutyric acid ester.    2-({1-[2-(1-isobutyryloxy-ethoxycarbonylamino)-4-methane-sulfinyl-butyldisulfanylmethyl]-cyclopentanecarbonyl}-amino)-succinic acid.    2-({1-[2-(1-isobutyryloxy-ethoxycarbonylamino)-4-methyl-sulfanyl-butyldisulfanylmethyl]-cyclopentanecarbonyl}-amino)-succinic acid.    Benzyl 2-({1-[2-(1-isobutyryloxy-ethoxycarbonylamino)-4-methanesulfinyl-butyldisulfanylmethyl]-cyclopentane-carbonyl}-amino)-succinic acid ester.    Benzyl 2-({1-[2-(1-isobutyryloxy-ethoxycarbonylamino)-4-methylsulfanyl-butyldisulfanylmethyl]-cyclopentanecarbonyl}-amino)-succinic acid ester.
The compounds of formulae (I) are obtained:
by condensation of a β-aminothiol protected on the amine function by a ter-butyloxycarbonyl group (Boc) (II) with a mercaptoalkanoic acid (III) by means of methoxycarbonylsulfenyl chloride.

The thereby obtained disulfide IV is coupled under standard peptide coupling conditions, preferably by action of TBTU (O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate) in the presence of DIEA (N,N-diisopropylethylamine), with an aminoester V, in order to lead to the compound VI.

Deprotection of the Boc group of the compound VI is carried out by action of formic acid and the thereby formed compound VII reacts on an activated ester of the carbamate VIII (R1—O-(p.NO2)Ph or R1—O-succinimide) in order to lead to the compound of formula (I).

Boc-β-aminothiol (II) is obtained in three steps from the corresponding commercial Boc-α-amino-acid, of absolute S configuration, with configuration retention according to a method well-known to one skilled in the art (J. Med. Chem., 35, 1992, 1259).

Two different methods are used for synthesizing the mercapto-alkanoic acid (III) depending on the nature of the R3 and R4 groups. If R4=H, the compound (III) is obtained from the corresponding malonic acid, which according to a method well-known to one skilled in the art (Ber. 57, (1924), 1116) is transformed into an acrylate (IX). Addition of thioacetic acid to the acrylate (IX) leads to the racemic derivative (X) which is for example esterified with methanol MeOH in the presence of EDCI (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide) and of DMAP (4-dimethylaminopyridine) or with methanol in the presence of thionyl chloride. By resolution with αchymotrypsin, it is possible to isolate the thioacetate with the S configuration (XII) (Bioorg. Med. Chem. Lett., 3, 1993, 2681). Alkaline hydrolysis of the thioester leads to the compound (III).

If R4≠H, the compound (III) is obtained from the corresponding carboxylic acid (XIII). The latter, treated with ethyl chloroformate in the presence of LDA (lithium diisopropyl amide) in THF (tetrahydrofurane), leads to the compound (XIV). The carboxylic acid function of (XIV) is transformed into a mixed anhydride and is reduced by NaBH4 into an alcohol (XV). Activation of the alcohol into a mesylate, and then substitution with potassium thioacetate leads to (XVI), which by alkaline hydrolysis gives (III).

Another synthesis route for the compound III may be suggested from the acid XIII. The latter is transformed into a t-butyl ester XVII, and by treatment with LDA in THF followed by carbonatation with CO2 leads to the derivative XVIII. The acid function of XVIII is then reduced into an alcohol in order to lead to the compound XIX. The sequence of reactions is identical with the one proposed in the preceding synthesis route.

Another object of the invention is the use as a drug of the compounds as defined earlier or obtained by a method as defined earlier. The object of the invention is also the pharmaceutical compositions containing as an active ingredient at least one of the compounds of general formula (I) or one of its salts or hydrates of its salts in combination with one or more inert supports or other pharmaceutically acceptable carriers.
These compounds have the properties of morphine substances, in particular analgesia, and in particular in its peripheral components (inflammatory, neurogenic and neuropathic components), the beneficial effects on behavior, in particular in the case of depression and/or anxiety, without having the major drawbacks of the latter (tolerance, addiction, respiratory depression, constipation, etc. . . . ). Thus, against exogenous opioid agonists interacting with delta receptors, the mixed inhibitors according to the invention have antidepressive effects without causing any risk of triggering epileptiform fits or convulsions and act rapidly (Baamonde A. et al., 1992, Jutkiewicz E. M. et al., 2005). These compounds act on the periphery at the nociceptors (Stein C. et al. (1993) Lancet 342 321-324 (2003) Nature Med., 9, 119-124). Advantageously, the compounds according to the invention, administered orally, do not penetrate into the central nervous system in significant concentrations; this is confirmed by the observation that the pre-administration of an antagonist—methylnaloxonium—incapable of crossing the blood brain barrier blocks the analgesic action of the compounds according to the invention.
The main application of the compounds according to the invention is therefore in the field of analgesia, antidepressives and of the treatment of addictions. These compositions may in particular be used as a potent analgesic in neuroinflammatory, neurogenic, neuropathic and nociceptive pains, and as an anti-depressive agent. Further, the compounds according to the invention of formula (I) have after oral administration shown quite interesting effects on animal models predicting activities in humans, in:                various neuropathic pains, diabetic neuropathy, neuropathy triggered by pre-administration of an anti-cancer agent, of an anti-viral agent (HIV-1), by zoster, etc. . . . ;        hyperalgesia and allodynia: neurophatic and neuroinflammatory allodynia and hyperalgesia, pain caused by the administration of formalin, carrageenin, Freund's adjuvant, hyperalgesia and allodynia produced by partial and unilateral compression of the sciatic nerve, by administration of tumoral cells in the bone marrow, etc. . . . .Analgesic drugs will refer to drugs which relieve or suppress pain without causing loss of sensations or of consciousness.        
As a summary, the present invention aims at treating symptoms corresponding not only to pains by excess of nociceptive stimulations, but also neuropathic or neurogenic pains which no longer have a physiological role, for example in the form of a signal, but which have become really pathological and chronic. Among the neurophatic and neurogenic chronic pains potentially sensitive to the action of the compounds of formula (I), mention may be made as non-limiting examples, of the pains of peripheral or central neuropathies resulting from nerve lesions of traumatic origin (for example, brachial plexus), of metabolic origin (for example, diabetes, alcoholic neuropathy), infectious origin (for example, zoster, herpes), toxic origin (for example, arsenic, lead), invasive origin (cancer pain) or congenital origin, of radiculopathic (for example, dorsolumbar or cervical) origins, neuralgic (trigeminal nerve); pains of phantom limbs; non-inflammatory joint pains (for example, arthrosis); fibromyalgias; rachidian pains; postoperative pains; medicinal pains (for example, from anti-tumoral agents, antiviral agents). The compounds according to the invention may also be used in the treatment of multiple sclerosis, which is an inflammatory disease of the central nervous system. Very interestingly, the compounds according to the invention have a long period of action, in particular equal to or greater than 120 minutes, more advantageously equal to or greater than 150 minutes, still more advantageously equal to or greater than 180 minutes.
The pharmaceutical compositions according to the invention may, as an example, be compositions which may be administered via an oral, nasal (administration with an aerosol), sublingual (administration by perlingual diffusion), rectal, parenteral, intravenous, and percutaneous route. As an example of compositions which may be administered orally, mention may be made of tablets, gelatin capsules, granules, microspheres, powders and oral solutions or suspensions. Also very interestingly, the compounds according to the invention have proved to be particularly suitable for oral administration. This administration route thus allows action of the composition according to the invention without penetrating into the central nervous system. This is particularly interesting for suppressing all the undesired effects resulting from activation of the opioid receptors in the brain and/or the spinal cord. The same applies when the composition comprises complementary compounds, which may have undesired effects on the central nervous system such as for example natural cannabinoids or synthetic derivatives. This also allows an increase in the cerebral bioavailability of the components of the combinations.
According to an advantageous alternative of the invention, the compounds of formula (I) are used in combination with cannabinoids. In the sense of the present invention, the expression “cannabinoids” refers to Δ9, synthetic agonists of the CB1 receptor or inhibitors of degradation of anandamide. The cannabinoids introduced into the compositions according to the invention are preferably Δ9 THC.
The object of the invention is also the combination of the novel compounds according to the invention with morphine or one of its derivatives. The object of the invention is also more particularly the combination of the novel compounds according to the invention with derivatives of Gaba, such as gabapentin or pregabalin.
The object of the invention is also a pharmaceutical composition comprising at least one compound of formula (I) as defined earlier, at least:                one cannabinoid derivative, in particular Δ9 THC, or a protector of its metabolism (review Piomelli et al., TIPS, 2000), and/or        morphine or one of its derivatives, and/or        a derivative of Gaba, such as gabapentin or pregabalin and a pharmaceutically appropriate excipient, in particular an appropriate excipient for administration via an oral, nasal, intravenous or transcutaneous route.        
The invention also relates to the use of at least one derivative of cannabinoids, in particular Δ9 THC, and/or morphine or one of its derivatives, and/or a derivative of Gaba, such as gabapentin or pregabalin, in a pharmaceutical composition in order to potentialize the analgesic and/or antidepressive effect of the compounds of formula (I) as defined earlier. The invention also relates to the use of a combination of at least one compound of formula (I) as defined earlier and of at least one derivative of cannabinoids, in particular Δ9 THC, and/or morphine, or one of its derivatives, and/or a derivative of Gaba, such as gabapentin or pregabalin, for preparing a drug intended for the treatment of depression and pain, in particular acute pain, inflammatory pain, neurogenic pain, neuropathic pain, psychogenic pain, allodynia.
Another object of the invention is a pharmaceutical composition comprising:
i) at least one compound of formula (I) as defined earlier
ii) at least one derivative of cannabinoids, and/or
iii) morphine or one of its derivatives, and/or
iv) at least one derivative of Gaba, such as gabapentin dr pregabalin, as combination products for simultaneous, separate use or spread out in time:
The effective dose of a compound of the invention varies according to many parameters, such as for example, the selected administration route, the weight, the age, the sex, the progression stage of the pathology to be treated and the sensitivity of the individual to be treated. Accordingly, the optimum dosage has to be determined, depending on parameters estimated to be relevant by the specialist in this field. The object of the invention is also a method for treating any of the diseases mentioned earlier, comprising the administration in a patient who requires such a treatment, of at least one of the compounds according to the invention or of a composition comprising at least one of these compounds. The compounds according to the invention may be used, in this method, either alone or combined notably with at least one of the compounds described earlier.
The invention will further be illustrated without being by any means limited by the examples hereafter. The list of the prepared compounds is given in Table I. For all of the compounds described in these examples 6, 8, 10, 12, 14, 16, 19 and 22.                R1 represents the        
—C(O)—O—CH(CH3)—OC(O)-iPr radical.                R6 represents a hydrogen atom.        
TABLE 1radicals of the examplesExampleR2R3R4R5R76—CH2—CH2—S—CH3BENZYLHH—CH(CH3)—OC(O)—O—C2H58—CH2—CH2—S—CH3benzylHHbenzyl10—CH2—CH2—S—CH3benzylHHH12—CH2—CH2—SO—CH3benzylHH—CH(CH3)—OC(O)—O—C2H514—CH2—CH2—SO—CH3benzylHHbenzyl16—CH2—CH2—SO—CH3benzylHHH19—CH2—CH2—S—CH3—(CH2)4——CH2—COOHH22—CH2—CH2—SO—CH3—(CH2)4——CH2—COOHH